Although much is known about the biochemical and morphologic substrates of the late stages of AD, relatively little is currently understood of the initial phases of this disorder and how those initial phases differ from what has been referred to as "normal aging". Based on our review of the literature, it is clear that prospective, longitudinal cognitive assessment is imperative for the identification of intact intellectual functioning as well as the earliest aspects of cognitive decline leading eventually to clinically apparent AD. Addressing these deficiencies in our knowledge, this project will perform detailed neuropathologic evaluations in order to characterize the extent and distribution of lesions in individuals judged, based on serial prospective cognitive assessment, to have either a) intact and stable cognitive functioning, b) early mild cognitive decline but with impairment insufficient to meet NINCDS Alzheimer's disease criteria or c) recent onset (early) Alzheimer's disease. Through the collection and morphologic examination of elderly subjects initially identified with intact cognitive function we anticipate having available to us significant numbers of brain specimens which will represent clinically verified normal controls of advanced age as well as individuals who appear to be in the earliest phases of AD. Our objective is to determine the pattern of the development of the cardinal lesions associated with the earliest phases of Alzheimer's disease. In our studies we will assess the extent and distribution of neurofibrillary tangles and senile plaques in the entorhinal cortex, hippocampus and selected neocortical regions of such cases. We will also investigate synaptic integrity through the use of anti-synaptophysin immunoreactivity as a potential correlate of early cognitive loss. Finally, using an antibody to vascular heparan sulphate proteoglycan we will explore evidence of alterations of the cerebral cortical microvasculature in these cases. We will cognitive impairment and to distinguish the regional pattern of these alterations. This project represents an unprecedented opportunity to explore issues of the neuropathologic substrates of normal aging and early phases of AD in an extremely elderly population.